Of isolates and isolation: Pseudomonas aeruginosa in adults with cystic fibrosis.
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Cross Infection↗
Biomedical subjects
D M Geddes
Publications and source records attributed to D M Geddes.
Gold as an oral corticosteroid sparing agent in stable asthma.
BACKGROUND: Patients with chronic severe asthma are often dependent on the long term prescription of oral corticosteroids. The use of steroids is associated with serious side effects. Physicians treating such patients continue to search for alternative therapies that reduce the need for chronic dosing with oral steroids. Gold compounds are immunosuppressive agents and have benefits in the treatment of a number of inflammatory disorders. They have therefore been identified as an potentially useful agents in the treatment of chronic severe asthma both in terms of possible efficacy and as steroid sparing agents. OBJECTIVES: The objective of this review was to assess the effects of adding gold to oral steroids in the treatment of chronic steroid dependent asthmatics. SEARCH STRATEGY: The Cochrane Airways Group trials register and reference lists of identified articles were searched. SELECTION CRITERIA: Randomised trials looking at the addition of gold compared to placebo in adult steroid dependent asthmatics. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data extraction was carried out by two reviewers independently. Study authors were contacted for missing information. MAIN RESULTS: Three trials fulfilled the criteria for inclusion in the review and a total of 376 patients were recruited into these studies. Data from 311 patients could be analysed. There was a small but significant treatment effect for gold in terms of steroid dose reduction (Peto Odds Ratio 0.51, 95% confidence intervals 0.31,0.83). No meta-analysis could be done for measures of lung function although overall there were few changes suggesting a positive benefit for gold. There were trends suggestive of adverse effects but no significant changes for gold treated patients with respect to proteinuria (Peto Odds Ratio 1.4, 95% confidence intervals 0.6, 3.3) dermatitis/eczema Peto Odds Ratio 2.1, 95% confidence intervals 0.9, 4.7). REVIEWER'S CONCLUSIONS: The changes seen in these trials are small and probably of limited clinical significance. Given the side effects of gold and necessity for monitoring the use of gold as a steroid sparing agent in asthma cannot be recommended.
Adrenal Cortex Hormones↗
Troleandomycin as an oral corticosteroid steroid sparing agent in stable asthma.
BACKGROUND: Patients with chronic severe asthma are often dependent on the long term prescription of oral corticosteroids. The use of steroids is associated with serious side effects. Physicians treating such patients continue to search for alternative therapies that reduce the need for chronic dosing with oral steroids. troleandomycin is a compound that is established as an effective antibiotic but may also have non antibacterial actions that may be useful in the treatment of asthma. OBJECTIVES: The objective of this review was to assess the effects of adding troleandomycin to oral steroids in the treatment of chronic steroid dependent asthmatics. SEARCH STRATEGY: The Cochrane Airways Group trials register and reference lists of identified articles were searched. SELECTION CRITERIA: Randomised trials looking at the addition of troleandomycin compared to placebo in adult steroid dependent asthmatics. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data extraction was carried out by two reviewers independently. Study authors were contacted for missing information. MAIN RESULTS: Three trials fulfilled the criteria for inclusion in the review and a total of 112 patients were recruited into these studies. Data from 90 patients were analysed. There was no treatment effect for troleandomycin in terms of steroid dose reduction (SMD -0.29, 95% CI -0.75, 0.17). For measures of lung function a meta-analysis of data derived from two of the included studies showed no benefits for added troleandomycin (SMD 0.06 95% CI -0.8, 0.9). REVIEWER'S CONCLUSIONS: There is insufficient evidence to support the use of troleandomycin in the treatment of steroid dependent asthma.
Administration, Oral↗
Cyclosporin as an oral corticosteroid sparing agent in stable asthma.
BACKGROUND: Patients with chronic severe asthma are often dependent on the long term prescription of oral corticosteroids. The use of steroids is associated with serious side effects. Physicians treating such patients continue to search for alternative therapies that reduce the need for chronic dosing with oral steroids. Cyclosporin is an immunosuppressive agent and has benefits in the treatment of a number of inflammatory disorders. It has therefore been identified as an potentially useful agent in the treatment of chronic severe asthma both in terms of possible efficacy and as a steroid sparing agent. OBJECTIVES: The objective of this review was to assess the effects of adding cyclosporin to oral steroids in the treatment of chronic steroid dependent asthmatics. SEARCH STRATEGY: The Cochrane Airways Group trials register and reference lists of identified articles were searched. SELECTION CRITERIA: Randomised trials looking at the addition of cyclosporin compared to placebo in adult steroid dependent asthmatics. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data extraction was carried out by two reviewers independently. Study authors were contacted for missing information. MAIN RESULTS: Three trials fulfilled the criteria for inclusion in the review and a total of 106 patients were recruited into these studies. Data from 98 patients could be analysed. There was a small but significant treatment effect for cyclosporin in terms of steroid dose reduction (SMD -0.5, 95% CI -1.0, -0.04). No meta-analyses could be performed for measures of lung function although one study showed small, but significant improvements in lung spirometry. REVIEWER'S CONCLUSIONS: The changes with cyclosporin are small and of questionable clinical significance. Given the side effects of cyclosporin, the evidence available does not recommend routine use of this drug in the treatment of oral corticosteroid dependent asthma.
Administration, Oral↗
Prospects for gene therapy in lung disease.
The past decade has brought significant advances in the field of gene therapy for both inherited and acquired diseases, especially with regard to respiratory disease. Barriers to gene transfer posed by the lung have led to the development of modifications of both vector and host in an attempt to increase the efficiency of transfer. Recently, progress has been made in both laboratory and clinical studies of gene therapy for cystic fibrosis, alpha1-antitrypsin deficiency and lung cancer.
Animals↗
Mucus altering agents as adjuncts for nonviral gene transfer to airway epithelium.
Nonviral vectors have been shown to be a safe and valid alternative to recombinant viruses for gene therapy of cystic fibrosis (CF). Nevertheless, gene transfer efficiency needs to be increased before clinical efficacy is likely in man. One barrier to increased efficacy is normal airway mucus. Using an ex vivo model of sheep tracheal epithelium, we show that this barrier can, in part, be overcome by treatment with the mucolytic agents, Nacystelyn or N-acetylcysteine using either a cationic lipid or a cationic polymer as the gene transfer agent. Further, in vivo application of either Nacystelyn or the anticholinergic glycopyrrolate, both clinically used agents, resulted in increased reporter gene expression in the mouse lung, but no significant correction of the bioelectric defect in CF null mice. These results, whilst unlikely to be sufficient in themselves to achieve clinically relevant gene therapy, may be a further useful step in the attainment of this goal.
Acetylcysteine↗
An in vitro model of neural trauma: device characterization and calcium response to mechanical stretch.
An in vitro model for neural trauma was characterized and validated. The model is based on a novel device that is capable of applying high strain rate, homogeneous, and equibiaxial deformation to neural cells in culture. The deformation waveform is fully arbitrary and controlled via closed-loop feedback. Intracellular calcium ([Ca2+]i) alterations were recorded in real time throughout the imposed strain with an epifluorescent microscopy system. Peak change in [Ca2+]i recovery of [Ca2+]i and percent responding NG108-15 cells were shown to be dependent on strain rate (1(-1) to 10(-1)) and magnitude (0.1 to 0.3 Green's Strain). These measures were also shown to depend significantly on the interaction between strain rate and magnitude. This model for neural trauma is a robust system that can be used to investigate the cellular tolerance and response to traumatic brain injury.
Analysis of Variance↗
Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence.
It is unclear whether inflammation in the cystic fibrosis (CF) lung relates predominantly to bacterial infection, or occurs as a direct consequence of mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. Interleukin (IL)-8 secretion from CF and non-CF cell lines, and from CF and non-CF human primary nasal epithelial cells incubated with or without Pseudomonas aeruginosa, was measured. Activation of nuclear factor-kappaB (NF-kappaB) in unstimulated CF and non-CF nasal epithelial cells, cell lines and murine tissues was measured by gel-shift assays. No significant difference in basal IL-8 production or NF-kappaB activation was observed between CF and non-CF primary nasal cells. However, CF cells exhibited a significantly (p<0.01) increased IL-8 secretion following P. aeruginosa stimulation. Equalization of the increased P. aeruginosa adherence observed in CF cells, to non-CF levels, resulted in comparable IL-8 secretion. Further, IL-8 production did not differ with mutations which result in either correctly localized CFTR, or in partial/total mislocalization of this protein. Similar levels of NF-kappaB activation were observed in a number of organs of wildtype and CF mice. Finally, IL-8 secretion and NF-kappaB activity were not consistently increased in CF cell lines. Cos-7 cell transfection with plasmids expressing deltaF508 or G551D mutant CFTR protein resulted in increased activation of a p50-containing NF-kappaB complex, but IL-8 secretion was similar to wild-type cells. The authors conclude that the stimulus produced by Pseudomonas aeruginosa is the predominant inflammatory trigger in their models.
Adolescent↗
Taking stock of gene therapy for cystic fibrosis.
The identification of the cystic fibrosis (CF) gene opened the way for gene therapy. In the ten years since then, proof of principle in vitro and then in animal models in vivo has been followed by numerous clinical studies using both viral and non-viral vectors to transfer normal copies of the gene to the lungs and noses of CF patients. A wealth of data have emerged from these studies, reflecting enormous progress and also helping to focus and define key difficulties that remain unresolved. Gene therapy for CF remains the most promising possibility for curative rather than symptomatic therapy.
Animals↗
Heat shock proteins in cancer therapy.
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Animals↗
Efficient gene transfer to airway epithelium using recombinant Sendai virus.
Clinical studies of gene therapy for cystic fibrosis (CF) suggest that the key problem is the efficiency of gene transfer to the airway epithelium. The availability of relevant vector receptors, the transient contact time between vector and epithelium, and the barrier function of airway mucus contribute significantly to this problem. We have recently developed recombinant Sendai virus (SeV) as a new gene transfer agent. Here we show that SeV produces efficient transfection throughout the respiratory tract of both mice and ferrets in vivo, as well as in freshly obtained human nasal epithelial cells in vitro. Gene transfer efficiency was several log orders greater than with cationic liposomes or adenovirus. Even very brief contact time was sufficient to produce this effect, and levels of expression were not significantly reduced by airway mucus. Our investigations suggest that SeV may provide a useful new vector for airway gene transfer.
Adenoviridae↗
Anti-inflammatory gene therapy directed at the airway epithelium.
Cystic fibrosis (CF) is characterised by chronic airway inflammation. Pro-inflammatory mediators in the lung are regulated by the transcription factor nuclear factor kappa B (NFkappaB). We have assessed the effect of adenovirus and liposome-mediated overexpression of the NFkappaB inhibitor IkappaBalpha, as well as liposome-mediated transfection with oligonucleotides resembling NFkappaB consensus binding sites (decoys) in a cystic fibrosis airway epithelial cell line (CFTE). Electrophoretic mobility shift assays (EMSA) were used to assess NFkappaB activity and secretion of the pro-inflammatory cytokine interleukin-8 (IL-8) was measured by ELISA. At a MOI of 30, Ad-IkappaBalpha significantly decreased IL-8 secretion to 60% and 43% of control unstimulated and TNF-alpha stimulated cells, respectively. At this MOI, approximately 70% of cells are transduced. EMSA showed an approximately 50% decrease in NFkappaB activation. Liposome-mediated transfection of IkappaBalpha did not reduce IL-8 secretion, probably due to low transfection efficiency (approximately 5% of cells). Liposome-mediated transfection of CFTE cells with rhodamine-labeled decoy oligonucleotides indicated a transfection efficiency close to 100%. TNF-alpha stimulated IL-8 secretion was reduced by approximately 40% using this approach. EMSA confirmed a significant decrease of NFkappaB activation. Decoy oligonucleotides may be a promising approach for reduction of NFkappaB-mediated pulmonary inflammation. Gene Therapy (2000) 7, 306-313.
Adenoviridae↗
Cationic lipid-mediated gene transfer to the growing murine and human airway.
Gene therapy in patients with cystic fibrosis may need to be commenced before the onset of lung disease which may be evident as early as 4 weeks after birth. We assessed the efficacy of cationic lipid-mediated transfer of a reporter gene, chloramphenicol acetyltransferase, in the growing murine and human respiratory tract. Gene expression was greater in adult mice (greater than 8 weeks old) compared with 9- and 16-day-old animals, despite a relatively greater proportion of complex delivered to the younger mice. Subsequent experiments compared 16-day-old and adult mice. Whilst higher gene expression occurred in the parenchyma compared with conducting airways in both groups, significantly greater expression was seen in the conducting airway of adult mice compared with 16-day-old animals. This expression persisted beyond 18 days in the adults but was undetectable in the younger group at this time-point. In an ex vivo model there was no difference in gene expression between the two groups. Further, no differences were observed in gene expression between growing (age 5 weeks to 14 years 8 months) and adult human lung tissue in either parenchyma or conducting airway. These data suggest age-dependent differences in gene transfer in vivo, which are not seen in an ex vivo setting. Proof-of-principle has been demonstrated for cationic-lipid mediated gene transfer to the growing human lung. Gene Therapy (2000) 7, 273-278.
Adolescent↗
Evaluation of patients undergoing lung volume reduction surgery: ancillary information available from computed tomography.
AIM: A number of imaging techniques have been used for the pre-operative assessment of patients for lung volume reduction surgery (LVRS). We evaluated whether data currently acquired from perfusion scintigrams and cine MR of the diaphragm are obtainable from high resolution CT (HRCT) of the thorax. MATERIALS AND METHODS: Thirty patients taking part in a randomized controlled trial of LVRS against maximal medical therapy were evaluated. HRCT examinations (n= 30) were scored for (i) the extent and distribution of emphysema; (ii) the extent of normal pulmonary vasculature; and (iii) diaphragmatic contour, apparent defects and herniation. On scintigraphy, (n= 28), perfusion of the lower thirds of both lungs, as a proportion of total lung perfusion (LZ/T(PERF)), was expressed as a percentage of predicted values (derived from 10 normal control subjects). On cine MR (n= 25) hemidiaphragmatic excursion and coordination were recorded. RESULTS: Extensive emphysema was present on HRCT (60% +/- 13.2%). There was strong correlation between the extent of normal pulmonary vasculature on HRCT and on perfusion scanning (r(s)= 0.85, P< 0.00005). Hemidiaphragmatic incoordination on MR was weakly associated with hemidiaphragmatic eventration on HRCT (P= 0.04). CONCLUSION: The strong correlation between lung perfusion assessed by HRCT and lung perfusion on scintigraphy suggests that perfusion scintigraphy is superfluous in the pre-operative evaluation of patients with emphysema for LVRS.
Adult↗
Case reports of death during pregnancy in patients with cystic fibrosis--three out of four patients were colonized with Burkholderia cepacia.
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Adult↗
Experience of totally implantable venous access devices (TIV ADs) in adults with cystic fibrosis over a 13-year period.
Totally implantable venous intravenous access devices (TIVADs) have an essential role in the frequent delivery of antibiotics in cystic fibrosis (CF) patients. This study at the Royal Brompton Hospital (RBH) reports the experience of TIVADs in patients attending the RBH adult CF unit implanted at the RBH and elsewhere over a 13-year period. The case notes of adult CF patients who had undergone TIVAD insertion were reviewed retrospectively. The patients were divided into those who had the insertion carried out at the RBH and those who had the device inserted elsewhere. All devices were cared for the at the RBH. A total of 115 devices in 74 patients were reviewed. The median duration of function of 109 devices was 1429 days (range 2-3989) or 3.9 years, with a total exposure of 91,188 days or 249.8 years. There was no significant difference between devices inserted at the RBH and those inserted elsewhere (P= 0.59). Thirty-four patients had devices installed without complications. Forty patients had complications in 62 devices. The incidence of complications was 34.5% at the devices inserted at RBH and 73.7% elsewhere (P<0.001). Of the 115 devices, mechanical complications occurred in 42 (36%) with a median time of diagnosis of 373 days (range 1-2554), infectious complications occurred in 16 (14%), with a median time of diagnosis of 413 days (range 40-2556) and symptomatic venous thrombosis occurred in four (3.5%). RBH-inserted devices had significantly fewer mechanical complications (P<0.001) compared with those inserted elsewhere. The group as a whole had fewer infectious complications than in most other reported series. We conclude that TIVADs provide effective and long-term intravenous access and have fewer complications if they are inserted and cared for at a centre with special expertise in their insertion and management.
Adolescent↗
Exhaled 8-isoprostane as a new non-invasive biomarker of oxidative stress in cystic fibrosis.
BACKGROUND: Cystic fibrosis is characterised by oxidative stress in the airways. Isoprostanes are prostaglandin isomers formed by free radical catalysed peroxidation of arachidonic acid. 8-Isoprostane is increased in interstitial lung diseases, asthma, chronic obstructive pulmonary disease, and adult respiratory distress syndrome. Exhaled nitric oxide (NO) and carbon monoxide (CO) are biomarkers of inflammation and oxidative stress in the airways, respectively. METHODS: Concentrations of 8-isoprostane in the breath condensate of 10 normal subjects and 19 patients with stable cystic fibrosis were measured using an enzyme immunoassay (EIA). Breath condensate is a non-invasive method of collecting airway secretions. Exhaled nitric oxide (NO) and carbon monoxide (CO) levels were measured by a chemiluminescence analyser. RESULTS: Concentrations of 8-isoprostane in the breath condensate of patients with stable cystic fibrosis were increased about threefold compared with normal subjects (42.7 (4.5) pg/ml vs 15.2 (1.7) pg/ml; p<0.005, 95% CI 14.6 to 40.9). 8-Isoprostane concentrations were negatively correlated with forced expiratory volume in one second in patients with cystic fibrosis (r = -0.61; p<0.005). Exhaled CO was also increased in patients with cystic fibrosis compared with normal subjects (6.7 (1.2) ppm vs 2.9 (0.3) ppm; p<0.05, 95% CI 0.2 to 7.4). 8-Isoprostane concentrations were significantly correlated with CO levels (r = 0.66; p<0.002). CONCLUSIONS: The results of this study show that oxidative stress is increased in cystic fibrosis and may be quantified by measuring 8-isoprostane concentrations in breath condensate.
Adult↗
In vivo transfer of bacterial marker genes results in differing levels of gene expression and tumor progression in immunocompetent and immunodeficient mice.
To optimize gene delivery for the treatment of malignant mesothelioma, expression of the beta-galactosidase marker gene was examined in a murine model of intraperitoneal malignant mesothelioma. The beta-galactosidase gene was delivered to the peritoneal cavity of tumor-bearing mice by various plasmid-liposome complexes or by replication-incompetent retrovirus, used alone or complexed to liposomes. In tumor samples from immunodeficient nude mice, moderate levels of gene expression were achieved by liposome-complexed plasmids. Retroviral gene delivery was more effective, and was increased nearly 10-fold by complexing the retrovirus to liposomes. In contrast, in tumor samples from immunocompetent CBA mice treated with the same vectors, no marker gene expression was detected. In immunodeficient mice, tumor growth was not affected by beta-galactosidase gene transfer. However, immunocompetent mice showed a significant decrease in tumor size and increase in survival time after beta-galactosidase delivery. Induction of cytotoxic T cells capable of lysing beta-Gal-transfected tumor cells suggests that tumor cells transduced with the bacterial beta-galactosidase gene may be eliminated in immunocompetent hosts. Our findings also indicate that plasmid-liposome complexes, which achieve a low level of gene expression, and retrovirus-liposome complexes, which result in nearly 100 times higher levels of gene expression in tumor cells in vivo, are similarly effective in inducing an antitumor immune response.
Animals↗